1. Field of the Invention
This invention is generally directed to a novel polymorph of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-α]-pyrimidin-7-yl}phenyl)acetamide which has activity over a wide range of indications, and is particularly useful for the treatment of insomnia, and to related processes, compositions and methods.
2. Description of the Related Art
The term “insomnia” is used to describe all conditions related to the perception of inadequate or non-restful sleep by the patient (Dement, International Pharmacopsychiatry 17:3-38, 1982). If left untreated, insomnia may result in disturbances in metabolism and overall body function including reduced productivity and significant changes in mood, behavior and psychomotor function, and a higher incidence of morbidity and mortality.
Traditionally, the management of insomnia includes treatment and/or mitigation of the etiological factors, improving sleep hygiene and the administration of hypnotic agents. The early hypnotic agents, such as barbiturates, while effective, elicited a spectrum of unwanted side effects and longer-term complications. For example, barbiturates have the potential to result in lethargy, confusion, depression and a variety of other residual effects many hours post dosing, as well as having a potential for being highly addictive.
During the 1980's, the pharmaceutical treatment of insomnia shifted away from barbiturates and other CNS depressants toward the benzodiazepine class of sedative-hypnotics. This class of sedative-hypnotic agents showed substantial effectiveness in producing a calming effect which results in sleep-like states in man and animals (Gee et al., Drugs in Central Nervous Systems, Horwell (ed.), New York, Marcel Dekker, Inc., 1985, p. 123-147) and had a greater safety margin than prior hypnotics, barbiturates or chloral hydrate (Cook and Sepinwall, Mechanism of Action of Benzodiazepines, Costa and Greengard (eds.), New York, Raven Press, 1975, p. 1-28). As with barbiturates, however, many benzodiazepines also possess side effects that limit their usefulness in certain patient populations. These problems include synergy with other CNS depressants (especially alcohol), the development of tolerance upon repeat dosing, rebound insomnia following discontinuation of dosing, hangover effects the next day, and impairment of psychomotor performance.
More recently, a new class of agents has undergone development. These agents are non-benzodiazepine compounds, which bind selectively to a specific receptor subtype of the benzodiazepine receptor. This receptor selectivity is thought to be the mechanism by which these compounds are able to exert a robust hypnotic effect, while also demonstrating an improved safety profile relative to the non-selective, benzodiazepine class of agents. The first of these agents to be approved by the United States Food and Drug Administration (FDA) for marketing in the United States was Ambien (zolpidem tartrate), which is based on the imidazopyridine backbone (see U.S. Pat. Nos. 4,382,938 and 4,460,592). In addition to Ambien, another compound known as Sonata (zaleplon), which is a pyrazolopyrimidine-based compound, has received FDA approval (see U.S. Pat. No. 4,626,538). Other non-benzodiazepine compounds and/or methods for making or using the same have also been reported (see, e.g., U.S. Pat. No. 4,794,185, 4,808,594, 4,847,256, 5,714,607, 4,654,347; 5,891,891).
While significant advances have been made in this field, there is still a need in the art for compounds that are effective as sedative or hypnotic agents generally, particularly in the context of treating insomnia. One such compound is N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-α]-pyrimidin-7-yl}phenyl)acetamide (referred to herein as “Compound 1”). Compound 1 is disclosed in U.S. Pat. No. 6,399,621 and has the following chemical structure: 
In addition, U.S. Pat. Nos. 6,384,221 and 6,544,999 are directed to polymorph Form I and Form II of Compound 1, while U.S. Pat. Nos. 6,472,528 and 6,485,746 are directed to synthesis and controlled release, respectively, of Compound 1.
While Compound 1 has proven particularly promising for the treatment of insomnia, improved forms of this compound are desired, particularly with regard to enhanced solubility, oral bioavailability, ability to be readily formulated, ease of synthesis, and/or physical stability. The present invention fulfills one or more of these needs and provides further related advantages.